Traumatic Brain Injuries: Pathophysiology and Potential Therapeutic Targets

REVIEW
published: 27 November 2019

doi: 10.3389/fncel.2019.00528
Traumatic Brain Injuries:

Pathophysiology and Potential
Therapeutic Targets
Si Yun Ng 1 and Alan Yiu Wah Lee 1,2 *
1
Neurobiology/Ageing Program, Centre for Life Sciences, Department of Physiology, Yong Loo Lin School of Medicine, Life
Sciences Institute, National University of Singapore, Singapore, Singapore, 2 School of Pharmacy, Monash University
Malaysia, Bandar Sunway, Malaysia
Traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality
amongst civilians and military personnel globally. Despite advances in our knowledge
of the complex pathophysiology of TBI, the underlying mechanisms are yet to be fully
elucidated. While initial brain insult involves acute and irreversible primary damage to the
parenchyma, the ensuing secondary brain injuries often progress slowly over months
to years, hence providing a window for therapeutic interventions. To date, hallmark
events during delayed secondary CNS damage include Wallerian degeneration of axons,
mitochondrial dysfunction, excitotoxicity, oxidative stress and apoptotic cell death of
neurons and glia. Extensive research has been directed to the identification of druggable
targets associated with these processes. Furthermore, tremendous effort has been
put forth to improve the bioavailability of therapeutics to CNS by devising strategies
for efficient, specific and controlled delivery of bioactive agents to cellular targets.
Here, we give an overview of the pathophysiology of TBI and the underlying molecular
mechanisms, followed by an update on novel therapeutic targets and agents. Recent
Edited by: development of various approaches of drug delivery to the CNS is also discussed.
Shuxin Li,
Temple University, United States Keywords: CNS trauma, secondary injuries, neuronal regeneration, cell penetrating proteins, biopolymers,
controlled drug release
Reviewed by:
Maria Dolores Ganfornina,
University of Valladolid, Spain
Xiaoming Jin, INTRODUCTION
Indiana University, Purdue University
Indianapolis, United States Traumatic brain injury (TBI) has been one of the leading causes of morbidity, disability and
*Correspondence: mortality across all ages (Bruns and Hauser, 2003; Dewan et al., 2018). Globally, more than
Alan Yiu Wah Lee 50 million individuals suffer from TBIs each year (Maas et al., 2017). As of 2005, approximately
alan.lee@monash.edu 3.17 million TBI survivors experience post-traumatic complications ranging from neurological,
psychosocial problems to long-term disability (Zaloshnja et al., 2008; Bazarian et al., 2009). The
Received: 10 July 2019 immense expenditure on clinical management of TBI patients and associated socioeconomic
Accepted: 13 November 2019
problems have imposed a heavy burden on the healthcare system and the society (Finkelstein
Published: 27 November 2019
et al., 2006). While increasing understanding of the clinical characteristics and the underlying
Citation: complex pathophysiological mechanisms of TBI has led to the development of novel and promising
Ng SY and Lee AYW
therapeutic approaches that show promising effects in preclinical studies and phase I/II trials,
(2019) Traumatic Brain Injuries:
Pathophysiology and Potential
majority of them turn out to be unsuccessful in phase III clinical trials. In fact, more than
Therapeutic Targets. 30 clinical trials of TBI pharmaceutical agents for diagnostics or therapeutic purposes have failed
Front. Cell. Neurosci. 13:528. over the past three decades. This review presents an overview of the molecular and cellular events
doi: 10.3389/fncel.2019.00528 in the pathogenesis of TBI. An update on potential druggable targets and new direction of treatment
Frontiers in Cellular Neuroscience | www.frontiersin.org 1 November 2019 | Volume 13 | Article 528

Ng and Lee Pathophysiology and Therapy of Traumatic Brain Injuries
is provided, followed by a discussion on various approaches to edema (Cernak and Noble-Haeusslein, 2009). Apart from the
delivering these therapeutics in a controlled manner. clinical characteristics mentioned above, post-traumatic stress
disorder is frequently associated with explosive blast TBI, and
CATEGORIES OF TBI research has shown a high occurrence rate in TBI survivors
(Risdall and Menon, 2011).
According to the unique physical mechanisms of insult, TBI can
be divided into three categories: (i) closed head; (ii) penetrating;
PATHOPHYSIOLOGY OF TBI
and (iii) explosive blast TBI. Clinical features of TBI include
prolonged coma, headache, nausea, aphasia, seizures, amnesia Damages of neuronal tissues associated with TBI fall into
and behavioral abnormalities such as aggression and anxiety, two categories: (i) primary injury, which is directly caused by
which occur within seconds to minutes after TBI; however, some mechanical forces during the initial insult; and (ii) secondary
of these manifestations can persist up to months and years (Bruns injury, which refers to further tissue and cellular damages
and Hauser, 2003; Andriessen et al., 2010). following primary insult.
Closed head TBI is typically caused by blunt impact incurred
mainly from motor vehicle accidents, falls and sports activities. Primary Brain Injuries
The incidence rate of this form of TBI is the highest amongst The immediate impact of different mechanical insults to the
the civilian population. The strong blunt and compression brain can cause two types of primary injuries: focal and diffuse
contact force disrupts normal functioning of the brain directly brain injuries. Studies have demonstrated that the co-existence
underneath the site of impact, thus causing immediate damage of both types of injuries is common in patients who suffered
to brain vasculature and neuronal cells. Brain displacement due from moderate to severe TBI (Skandsen et al., 2010); however,
to vibrations and shocks generated during the impact can also diffuse axonal injury (DAI) accounts for approximately 70% of
lead to compression of brain tissues and reduction of cerebral TBI cases. As a consequence of lacerations, compression and
blood flow. Both mechanisms eventually result in focal localized concussion forces, closed head TBI and penetrating TBI exhibit
contusions or diffuse injury to other brain regions. focal brain damage with evidence of skull fracture and localized
Penetrating TBI results when a foreign body penetrates the contusion at the core of injury site (coup; Schmidt et al., 2004).
skull and traverses through the dura into brain parenchyma. Necrotic area of neuronal and glial cells is concentrated at the
Similar to closed head TBI, laceration of brain tissues primarily coup with compromised blood supply, causing the occurrence of
causes focal damages, intracranial hemorrhage, cerebral edema hematoma, epidural, subdural and intracerebral hemorrhages at
and ischemia. The invasion of fast-moving projectile can lead confined layers of the brain. Secondary contusion may develop
to tissue cavitation, which further exacerbates injuries. The type in tissues opposite to or surrounding the coup (contre-coup) due
and severity of neurological damage are dependent on the size, to secondary impact when the brain rebounds and strikes the
speed, route and strength of the external body penetrating the skull (Schmidt et al., 2004). Depending on the severity of the
brain. Due to exposure of brain tissue to the harsh environment, injury, it can lead to cognitive deficits, behavioral changes and
the chance of infection is relatively high in this form of TBI. hemiparesis. In contrast to focal injury, the main mechanism of
With the invasive nature of this type of injury, penetrating TBI is diffuse brain injury is non-contact forces of rapid deceleration
associated with acute medical complications such as respiratory and acceleration which cause shearing and stretching injury
failure, pneumonitis, hypotonia and cerebrospinal leakage in in cerebral brain tissues. The strong tensile forces damage
comparison to closed head TBI (Black et al., 2002). neuronal axons, oligodendrocytes and blood vasculature, leading
With the high prevalence of casualties suffering from to brain edema and ischemic brain damage (Smith et al., 2003).
war-related TBI in the 20th century mainly in Afghanistan The hallmark feature of diffuse TBI is extensive damage of
and Iraq, explosive blast TBI has recently been considered axons predominantly in subcortical and deep white matter
as a new category (Warden, 2006). Unlike closed head and tissue such as the brain stem and corpus callosum, which
penetrating TBI, the brain is compromised by rapid pressure involves impairment of axonal transport and degradation of
shock waves generated from explosion, which transmits a axonal cytoskeleton. Notably, these axonal damages can persist
tremendous amount of energy from the skull into the enclosed up to months following TBI, suggesting an association with
brain parenchyma (Ling and Ecklund, 2011). The effects of delayed secondary pathology of hemorrhages and brain edema
blast injury can be divided into different patterns: primary (Saatman et al., 2008). The degree of axonal injury and neuronal
(shock wave causing internal damage), secondary (penetrating), degeneration determines the severity of TBI. Interestingly, while
tertiary (physical injury by blast wave) and quaternary (other explosive blast TBI is a result of shock waves instead of
than the first three classes) depending on the injury outcome inertial forces, it displays the characteristics of a typical diffuse
at different stages of blast-induced injury (Cernak and Noble- brain injury.
Haeusslein, 2009; Risdall and Menon, 2011). Kinetic energy
generated in the blast causes deformation of the brain, thus Secondary Brain Injuries
creating a widespread diffuse injury in both the gray and The biochemical, cellular and physiological events that
the white matter, leading to neuronal cell death, axonal occur during primary injury often progress into delayed
injury, compromised blood-brain-barrier (BBB), vasospasm, and prolonged secondary damages which can last from
pseudoaneurysm formation, hyperemia, contusion and cerebral hours to years. Mechanistically, a number of factors

contribute to secondary injuries, which include excitotoxicity, death over an extended period, which correlate with increased
mitochondrial dysfunction, oxidative stress, lipid peroxidation, mortality rate and worsened 6-month neurological outcome
neuroinflammation, axon degeneration and apoptotic cell death (Deshpande et al., 2008; Chamoun et al., 2010).
(Ray et al., 2002; Figure 1).
Mitochondrial Dysfunction
Excitotoxicity Mitochondrial dysfunction is one of the hallmark events of
Studies in both animals and humans have demonstrated that BBB TBI (Xiong et al., 1997), which contributes to metabolic
breakdown and primary neuronal cell death during TBI induce and physiologic deregulations that cause cell death. The
excessive release of excitatory amino acids such as glutamate and sequestration of intracellular Ca2+ and influx of excessive
aspartate from presynaptic nerve terminals (Faden et al., 1989; ions into mitochondria results in the production of ROS,
Chamoun et al., 2010). The presence of excessive glutamate depolarization of mitochondrial membrane and inhibition of
during TBI is also contributed by a failure of glutamate re-uptake ATP synthesis (Lifshitz et al., 2004; Singh et al., 2006). This leads
due to the dysfunction of glutamate transporters. There has been to the breakdown of electron transport chain and impairment
evidence that shows a 40% decline in the expression of astrocytic of oxidative phosphorylation processes, thus disrupting the
sodium-dependent glutamate transporters GLAST (EAAT1) restoration of metabolic reactions for cell survival and regulation
and GLT-1 (EAAT2) within 24 h following TBI, leading to a of calcium cycle. Mitochondrial permeability transition pore
significant decrease in the resorption of glutamate (Rao et al., (mPTP) is also activated under these conditions. Conformational
1998; van Landeghem et al., 2006). These excitatory amino change of an inner membrane protein adenine nucleotide
acids activate both ionotropic glutamate receptors (iGluRs) translocator (ANT) upon binding to cyclophilin D leads to
and metabotropic glutamate receptors (mGluRs). Members of the opening of mPTP and an increase in inner membrane
iGluRs such as N-methyl-d-aspartate (NMDA) receptor and permeability (Susin et al., 1998; Naga et al., 2007; Tsujimoto and
α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) Shimizu, 2007), further contributing to mitochondrial pathology.
receptor are ligand-gated ion channels that allow Na+ , K+ and Electron microscopy analysis of mitochondria has revealed
Ca2+ ionic flux upon binding to glutamate, causing membrane significant swelling and structural damages such as disruption of
depolarization in neurons (Meldrum, 2000). NMDA receptor cristae membrane and loss of membrane potential. Furthermore,
is peculiar in that it is also voltage-gated and is permeable to mitochondrial proteins such as cytochrome c and apoptosis-
Ca2+ ions. Hyperactivation of AMPA and NMDA receptors by inducing factor (AIF) which play crucial roles in apoptotic
excessive glutamate has been shown to alter ion homeostasis cell death are released into the cytosol (Sullivan et al., 2002;
in postsynaptic neurons by allowing influx of extracellular Singh et al., 2006).
Ca2+ and Na+ ions (Sun et al., 2008; Brustovetsky et al.,
2010). NMDA-induced surge in intracellular Ca2+ initiates the Release of Reactive Oxygen Species and Lipid
activation of various downstream signaling molecules, including Peroxidation
Ca2+ /calmodulin-dependent protein kinase II (Folkerts et al., Accumulating evidence suggests that oxidative stress contributes
2007), mitogen activated protein kinases (MAPK; Lu et al., to TBI pathogenesis to a significant extent. Endogenous ROS
2008) and protein phosphatases (Bales et al., 2009). Protein and free radicals are constantly generated following TBI from
kinase C is also activated to couple to NMDA receptors, thereby various sources, like enzymatic processes, activated neutrophils,
enhancing Ca2+ influx into postsynaptic neurons (Luo et al., excitotoxic pathways and dysfunctional mitochondria (Xiong
2011). Similarly, activation of AMPA receptors can also trigger et al., 1997; Shohami and Kohen, 2011). On the other hand,
the MAPK pathway through calcium-dependent mechanisms the accumulation of Ca2+ after TBI increases the activity of
(Schenk et al., 2005). Activation of NMDA receptors by nitric oxide synthases (NOS), which aids in the production
glutamate promotes the production of reactive oxygen species of NO. The reaction between excessive NO and free radical
(ROS; Reynolds and Hastings, 1995; Girouard et al., 2009) superoxides results in the formation of peroxynitrite (PN),
and nitric oxide (NO; Sattler et al., 1999), which further which induces oxidative damage and can be measured by
exacerbates secondary cell injury. Unlike iGluRs, mGluRs detecting oxidative markers such as 3-nitrotyrosine (3-NT) and
regulate Ca2+ and downstream signaling via GTP-binding 4-hydroxynonenal (4-HNE; Hall et al., 2004). In vivo studies
proteins. Glutamate stimulation of mGluRs triggers the have shown an increase in the levels of 3-NT and 4-HNE in
activation of phospholipase C/inositol-1,4,5-triphosphate, which ipsilateral cortex and hippocampus (Hall et al., 2004; Singh et al.,
in turn mobilizes Ca2+ release from intracellular stores into 2006; Deng et al., 2007; Ansari et al., 2008a) after TBI. Oxidative
the cytosol and triggers the signaling cascades in injured CNS stress is also associated with impaired synaptic plasticity in
(Weber, 2012). Excessive Ca2+ in the cytosol also activates a injured cortex and hippocampus, with concomitant loss of the
number of proteins that cause apoptotic cell death, such as synaptic proteins synapsin-1 and PSD-95 from 24 to 48 h
calcineurin, calpain and caspases. In addition, accumulation post-injury (Ansari et al., 2008a,b). These ROS react not only
of Ca2+ and ROS leads to impairment of mitochondrial with proteins and DNA but also polyunsaturated fatty acids
function, further aggravating the deregulation of Ca2+ and ROS in membrane phospholipids which in turn form lipoperoxyl
homeostasis. In summary, excessive stimulation of glutamate radicals, further damaging cell membranes. The increase in
receptors due to massive release of excitatory neurotransmitters permeability of mitochondria membrane and the oxidation of
leads to post-traumatic oxidative stress and excitotoxic cell membrane proteins leads to an alteration of ion transport.

FIGURE 1 | Schematic representation of pathophysiology of traumatic brain injury (TBI). BBB dysfunction caused by TBI insult allows transmigration of activated
leukocytes into the injured brain parenchyma, which is facilitated by an upregulation of cell adhesion molecules. Activated leukocytes, microglia and astrocytes
produce ROS and inflammatory molecules such as cytokines and chemokines that contribute to demyelination and disruption of axonal cytoskeleton, leading to
axonal swelling and accumulation of transport proteins at the terminals, hence compromising neuronal activity. Progressive axonal damage results in
neurodegeneration. In addition, astrogliosis at the lesion site causes glial scar formation, which creates a non-permissive environment that impedes axonal
regeneration. On the other hand, excessive accumulation of glutamate and aspartate neurotransmitters in the synaptic space due to spillage from severed neurons,
glutamate-induced aggravated release from pre-synaptic nerve terminals and impaired reuptake mechanisms in traumatic and ischemic brain activate NMDA and
AMDA receptors located on post-synaptic membranes, which allow the influx of calcium ions. Together with the release of Ca2+ ions from intracellular store (ER),
these events lead to the production of ROS and activation of calpains. As a result of mitochondrial dysfunction, molecules such as apoptosis-inducing factor (AIF)
and cytochrome c are released into the cytosol. These cellular and molecular events including the interaction of Fas-Fas ligand ultimately lead to caspase-dependent
and -independent neuronal cell death. BBB, blood-brain-barrier; ROS, reactive oxygen species; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;
NMDA, N-methyl-d-aspartate; ER, endoplasmic reticulum.

Abnormal Ca2+ accumulation, for instance, has profound 2006). As the hallmark of DAI, these retraction bulbs can
implications in prolonged excitotoxicity (Praticò et al., 2002). be detected by the axonal markers β-amyloid precursor
In short, the persistent release of highly reactive oxygen free protein (β-APP) and neurofilament (NF) as early as 1 day
radicals and the associated elevation in the level of ROS-mediated post-TBI and up to 2 weeks in experimental models of
lipid peroxidation in TBI impose adverse effects in brain diffuse TBI. Retraction bulbs are predominantly found in
plasticity, cerebral blood flow, and promote immunosuppression corpus callosum and pyramidal tracts of brain stem (Pierce
(Ansari et al., 2008a). et al., 1996; Hellewell et al., 2010), though their presence
in hippocampus, cortex, cingulum, the internal and external
Neuroinflammation
capsule has also been reported (Hellewell et al., 2010).
Within the acute post-TBI period of 24 h, dysfunction of BBB
Hellewell et al. (2010) has demonstrated the association
allows infiltration of circulating neutrophils, monocytes and
between axonal damage in corpus callosum and infiltration of
lymphocytes into the injured brain parenchyma (Lotocki et al.,
neuroinflammatory cells (microglia and macrophages) which
2009). Analysis of cerebrospinal fluid (CSF) and post-mortem
would lead to disruption of blood vasculature, degradation
tissue of TBI patients (Buttram et al., 2007; Frugier et al., 2009;
of axons, damage of oligodendrocytes and deformation of
Goodman et al., 2009) and tissue of TBI rodents (Ahn et al.,
white matter.
2004; Lotocki et al., 2009; Semple et al., 2010) revealed that these
polymononuclear leukocytes release complement factors and
Glial Scar and Myelin-Associated Axonal Growth
pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α, as
Inhibitors
evident by an increase in the corresponding mRNA and protein
Insults to the CNS often trigger activation and proliferation of
24 h post-trauma. Sustained upregulation of various cytokines
astrocytes. The resulting reactive astrocytes infiltrate into the
was found to be associated with altered BBB permeability,
lesion site and undergo reactive astrogliosis, which involves
formation of edema and neurological deficits. As a member of the
hypertrophy and an increase in the complexity of their processes.
Fas superfamily, TNF-α interacts closely with Fas ligand which
Intermingle of astrocytic processes with oligodendrocytes,
in turn activates caspases that are essential for programmed cell
meningeal cells, microglia and fibroblasts gradually develop into
death (Morganti-Kossmann et al., 2002). Chemokines such as
a scar-like structure, which has long been implicated as a major
MIP-α, MCP-1 and IL-8 (CXCL8) are significantly upregulated
physical impediment to axonal regeneration and counteracts TBI
post-trauma, which act synergistically and are involved in further
recovery (Fawcett and Asher, 1999). Recent findings however
recruitment of leukocytes to the injury site (Kossmann et al.,
suggest that chondroitin sulfate proteoglycans (CSPGs) such
1997; Buttram et al., 2007; Bye et al., 2007; Semple et al., 2010).
as neurocan and versican in glial scar, which are upregulated
Furthermore, upregulated expression of ICAM-1 and VCAM-
following CNS injury, are in fact the molecular barrier that
1, which are ligands for endothelial and leukocyte cell adhesion
impedes axonal regeneration (Asher et al., 2000, 2001, 2002).
receptors facilitates the interaction of leukocytes and immune
Together with other inhibitory molecules in glial scar, such
cells with endothelium, hence promoting their recruitment to the
as tenascins and semaphorin 3A, these molecules constitute a
injured site (Carlos et al., 1997; Rancan et al., 2001). Prolonged
non-permissive milieu for axonal growth (Zhang et al., 1997;
and delayed neuroinflammation in turn recruits macrophages,
Pasterkamp et al., 2001; De Winter et al., 2002). Interestingly,
activates resident microglia cells and promotes astrogliosis
RhoA pathway is implicated in mediating their inhibitory
(Morganti-Kossmann et al., 2007; Bye et al., 2011). Progressive
effects because blockade of RhoA activity or its downstream
phagocytosis and persistent inflammatory responses are evident
effectors promotes permissive growth of neuronal axon on these
by the accumulation of macrophages and activated microglia
substrates (Winton et al., 2002; Monnier et al., 2003). The
in TBI survivors years after injury (Gentleman et al., 2004;
signaling cascades triggered by semaphorin 3A in glial scar, for
Johnson et al., 2013).
instance, involve neuropilin-plexin receptor complex and the
Axonal Degeneration activation of Rho GTPases, which are believed to induce growth
Wallerian degeneration is widely observed within minutes after cone collapse through the regulation of F-actin cytoskeleton
DAI. Immediate mechanical damage leads to disorganization (Pasterkamp and Kolodkin, 2003).
of axonal cytoskeletal network, which consists of longitudinally In addition, damaged myelin in severed axon causes the
oriented neurofilaments and microtubules (Tang-Schomer et al., exposure of axon outgrowth inhibitors such as myelin-associated
2010). Together with constant calcium-mediated proteolysis, glycoprotein (MAG), oligodendrocyte myelin glycoprotein
acute axonal damage can progress and develop into delayed (OMgp) and Nogo-A (Chaudhry and Filbin, 2006). Intriguingly,
and secondary axotomy days and months following the initial these myelin-associated inhibitors bind specifically to Nogo
trauma, which is characterized by degradation of myelin sheath, receptor (NgR) complex on neuronal membrane, which consists
impairment of axonal transport and accumulation of axonal of the co-receptors p75NTR , Troy and LINGO-1 (Wang et al.,
transport proteins (Povlishock, 1992; Saatman et al., 2003; 2002; Mi et al., 2004; Park et al., 2005). These inhibitors
Büki and Povlishock, 2006). Formation of retraction bulbs due trigger the activation of RhoA GTPases and Rho kinase that
to disassociation of axonal connections and accumulation of can induce growth cone collapse and retraction of neurites
axonal transport proteins in the node can eventually result (Nash et al., 2009). In fact, post-mortem analysis of traumatized
in prolonged swelling of injured axons and apoptotic cell human brain tissues revealed an increase in the expression
death of neurons and oligodendrocytes (Büki and Povlishock, of RhoA and RhoB proteins in reactive glia and swollen

neurites, which could persist up to months after TBI (Brabeck lysosome-dependent degradation pathway (Mizushima et al.,
et al., 2004). In experimentally-induced focal brain injury, 2008). Autophagy plays an important role in cytoprotection,
active RhoA was found to be accumulated at the lesioned maintenance of cell stability and survival through elimination
cortex and hippocampus 18 h post-trauma (Dubreuil et al., of abnormal intracellular proteins or organelles when cells are
2006; Zhang Z. et al., 2008). While the precise role of severed or under stress, though it is also implicated in the
Rho GTPase pathway in TBI requires further investigation, regulation of apoptotic cell death, inflammation, and adaptive
its involvement in related forms of CNS injuries like spinal immune responses (Maiuri et al., 2007). Macroautophagy is
cord injury and cerebral ischemia has been well established amongst the best-characterized autophagy subtype, which is a
(Dubreuil et al., 2003; Yagita et al., 2007). It is suggested multi-step process that involves sequestration of cytoplasmic
that RhoA not only inhibits axonal regeneration but also components such as damaged organelles and proteins in double-
plays a role in apoptotic responses after TBI as constant membrane structures known as autophagosomes, followed
upregulation of active RhoA impairs regeneration of axons by fusion with lysosomes whereby proteolytic degradation
and neurites. occurs (Mizushima, 2007). This autophagic flux is under tight
regulation by members of the autophagy-related (ATG) protein
Apoptotic Cell Death
family such as ATG9, the autophagosome marker protein
Apoptotic cell death of neurons and oligodendrocytes are
LC3-II that is involved in the recruitment of substrates for
hallmarks of secondary brain injury (Beer et al., 2000; Grady
autophagic degradation, and the beclin 1 protein which is
et al., 2003). Smith et al. (1997) have reported that neuronal
essential for autophagosome formation. Accumulating evidence
cell death is evident in human hippocampus for up to 1 year
suggests the involvement of autophagy-lysosome pathway in
after TBI. These apoptotic events involve the activation of
secondary injury processes of TBI and SCI, though whether
cysteine proteases such as caspases and calpain, and can be
it plays beneficial or detrimental roles remains controversial.
triggered by the interaction of various neurochemical, cellular
Upregulation of autophagic markers and accumulation of
and molecular pathways such as extracellular signal-regulated
autophagosomes have been observed in early phase of secondary
kinase (ERK), p38 MAPK, janus kinase/signal transducer and
injury, which correlate with severity and can persist for weeks
activator of transcription (JAK/STAT; Kawasaki et al., 1997; Mori
to months (Diskin et al., 2005; Clark et al., 2008; Sakai
et al., 2002; Raghupathi, 2004; Zhao et al., 2011). Apoptotic
et al., 2014; Au et al., 2017). The increase in autophagic
cell death caused by caspase-dependent mechanisms can be
flux, which can be potentiated by rapamycin is associated
induced by the extrinsic death receptor pathway or the intrinsic
with improved neurobehavioral function, enhanced neuronal
mitochondrial pathway (Stoica and Faden, 2010). Extrinsic
survival, reduced inflammation and gliosis in injured brain
pathway involves the interaction of TNF and Fas with their
(Erlich et al., 2007; Zhang Y. B. et al., 2008). In fact,
specific receptors on cell surface, whereas intrinsic pathway is
many neuroprotective drugs alleviate TBI-induced secondary
activated when cytochrome c is released after mitochondrial
injury by activating autophagy (Ding et al., 2015; Gao
depolarization (Sullivan et al., 2002). Cytochrome c forms an
et al., 2017; Zhang et al., 2017). Nonetheless, lysosomal
ATP-dependent complex with apoptotic activating protein-1
function is often found to be compromised in TBI, which
and ATP in the cytosol. Both mechanisms activate the caspase-
involves an increase in lysosomal membrane permeability. This
dependent downstream signaling through upregulation and
leads to an impairment of autophagic flux and pathological
activation of caspase 8 and 9 which ultimately lead to the cleavage
accumulation of autophagosomes and their cargo, causing
and activation of caspase 3 (Clark et al., 1999, 2000; Zhang et al.,
neuronal cell death and exacerbating the severity of trauma
2003). On the other hand, caspase-independent apoptosis in TBI
(Sarkar et al., 2014).
can be initiated by the activation of calpains through proteolysis
of cytoskeletal proteins such as spectrin and NF proteins
(Deng et al., 2007) and the release of mitochondrial proteins POTENTIAL THERAPEUTICS
such as AIF (Hong et al., 2004), Smac/DIABLO, Omi/HtrA2 ,
Since primary injuries in TBI usually involve acute physical
poly (ADP-ribose) polymerase-1 and endonuclease G (Mammis
damages and necrotic cell death that are unlikely to be
et al., 2009). These mitochondrial proteins translocate into the
reversible, treatment regimens mainly aim to stabilize the
nucleus and activate downstream signaling molecules, resulting
site of injury and prevent it from secondary damage. As
in DNA damage and chromatin condensation in neuronal
mentioned above, secondary injuries are caused by an array
and glial cells. Apoptosis can be regulated by anti-apoptotic
of risk factors and develop in a progressive manner. This
proteins such as the Bcl-2 family and death-inducing factors
provides a window for therapeutic intervention of events that
such as Bax (Wennersten et al., 2003). Studies have shown
could induce further loss of neurons and glial cells beyond
that Bcl-2 protein expression is significantly upregulated in
the injury epicenter, which include persistent inflammatory
brain tissues of TBI patients (Clark et al., 1999). Similarly, a
response, excitotoxicity, oxidative stress and apoptotic cell death
25% increase in Bax protein was observed in traumatic rat
(Ray et al., 2002). Extensive research has been dedicated to
brain (Raghupathi et al., 2003).
gain a better understanding of the underlying mechanisms
Impairment of Autophagy and Lysosomal Pathways of secondary brain injuries (Table 1), in the hope of
Autophagy is an adaptive homeostatic process that regulates developing more effective therapeutic strategies to target
the turnover of cellular organelles and proteins through multiple stages.

TABLE 1 | Summary of the pathophysiology, therapeutic targets and potential therapies in traumatic brain injuries.
Pathophysiology Therapeutic targets Potential therapies Clinical trials Treatment efficacy
Excitotoxicity Glutamate receptors, Ca2+ Glutamate receptor antagonists Dexanbionol: NCT00129857 Neuroprotective effect in
channels, HU211 (Dexanbionol; Nadler experimental TBI but not
calpains/caspases et al., 1993, 1995; Shohami et al., efficacious in clinical trials
1995), MK 801 (Goda et al., (Maas et al., 2006)
2002; Imer et al., 2009), NBQX
(Follett et al., 2000)
Ca2+ channel inhibitors

(S)-emopamil (Okiyama et al.,
1992, 1994), SNX-111
(Ziconotide; Samii et al., 1999)
and SNX-185 (Lee et al., 2004;
Shahlaie et al., 2009), Nimodipine
(Veng et al., 2003), Nicarpine
(Compton et al., 1990)
Calpain/caspase inhibitors
MDL 28170 (Kawamura et al.,
2005), Z DEVD-fmk (Knoblach
et al., 2004)
Mitochondrial dysfunction ROS, mPTP components, Neuroprotectants NeuroSTAT: NCT01825044; Anti-oxidative effect reduces
cytochrome c Cyclosporine A (Okonkwo and EudraCT 2012-000756-34 axonal damage and
Povlishock, 1999; Sullivan et al., mitochondrial dysfunction in
1999) animal TBI. Phase IIa trial
confirmed drug safety and
BBB permeability (Kelsen
et al., 2019)
Oxidative stress ROS Anti-inflammatory agents Methylprednisolone: Anti-inflammatory and
Methylprednisolone (Hall, 1992) ISRCTN74459797; anti-oxidative effects. Early
NCT00004759 administration of
Neuroprotectants methyl-prednisolone is
Cyclosporine A (Turkoglu et al., associated with higher risk of
2010) death in patients with head
injury (Thompson and Bakshi,
2005)
Neuroinflammation Pro-inflammatory Anti-inflammatory agents Minocycline: NCT01058395; Anti-inflammatory and

chemokines, complement Minocycline (Tikka and NCT02802631 anti-apoptotic effects.
factors Koistinaho, 2001; Bye et al., Erythropoietin shows no
2007; Filipovic and Zecevic, beneficial effect in moderate
2008; Ng et al., 2012) or severe TBI patients (Nichol
et al., 2015)
Anti-apoptosis Erythropoietin:
Erythropoietin (Yatsiv et al., 2005; NCT00987454;
Chen et al., 2007) NCT00313716
Axonal degeneration Calpains, NOS Glutamate receptor antagonists Anti-apoptotic,

NBQX (Follett et al., 2000; Goda anti-inflammatory,
et al., 2002) neuroprotection
Calpain inhibitors
MDL 28170 (Buki et al., 2003; Ai
et al., 2007; Czeiter et al., 2009)
Anti-inflammatory agents
Minocycline (Siopi et al., 2011)
Neuroprotectants
Cyclosporine A (Okonkwo and
Povlishock, 1999; Okonkwo
et al., 1999)
Anti-apoptosis
Erythropoietin
(Yatsiv et al., 2005)
(Continued)

TABLE 1 | Continued
Patho-physiology Therapeutic targets Potential therapies Clinical trials Treatment efficacy
Stem cells therapy

Marrow stromal cells (Mahmood
et al., 2004b), mesenchymal stem
cells (Kim et al., 2009), fetal stem
cells (Riess et al., 2002; Skardelly
et al., 2011)
Neurotrophic factors
BDNF, NGF (Kromer, 1987; Dixon
et al., 1997; Sinson et al., 1997),
bFGF (Dietrich et al., 1996), EGF
(Laskowski et al., 2005)
Apoptosis Caspases, calpains, Calpain/caspase inhibitors Anti-apoptosis

cytochrome c MDL 28170 (Kawamura et al.,
2005; Thompson et al., 2010), Z
DEVD-fmk (Clark et al., 2000;
Knoblach et al., 2004)
Anti-apoptosis
Erythropoietin (Yatsiv et al., 2005;
Liao et al., 2008)
Stem cells therapy

Mesenchymal stem cells (Kim
et al., 2009)
Impaired mTOR Rapamycin (Erlich et al., 2007; Neuroprotection

autophagy-lysosomal Zhang Y. B. et al., 2008), Luteolin
pathway (Xu et al., 2014)
Myelin-derived inhibitors Nogo and NgR, MAG, Myelin inhibitors IN-1 antibody: NCT03935321 Intrathecal administration of
OMgp, RhoA IN-1 antibody against Nogo-A (Yu anti-Nogo-A to SCI patients is
et al., 2008), DNA vaccine against well-tolerated in phase I trial
myelin inhibitors (Zhang et al., (Kucher et al., 2018)
2009)
RhoA inhibitors Cethrin (BA-210: Treatment of SCI patients with

C3 transferase (Tan et al., 2007; NCT00500812; VX-210: Cethrin is well-tolerated in
Höltje et al., 2009; Boato et al., NCT02669849) phase I/IIa trial (McKerracher
2010) and Anderson, 2013)
Glial scar CSPGs, tenascins, Glial scar Chondrotinase ABC

semaphorins Chondrotinase ABC (Bradbury promotes axon outgrowth
et al., 2002; Barritt et al., 2006; and regeneration in SCI
Lin et al., 2008) animals
RhoA inhibitor
C3 transferase (Monnier et al.,
2003)
Protection of Neurons and Glia Against (dizocilpine) has been shown to reduce oxidative stress, microglia
activation, oxidative stress, axonal damage and neuronal cell
Excitotoxicity death (Goda et al., 2002; Imer et al., 2009). Importantly, these
Glutamate Receptor Antagonists effects are associated with an improvement of cognitive function
HU-211 (dexanabinol), a non-competitive NMDA receptor and neurological outcome (Shohami et al., 1995, 1997). Similarly,
antagonist, has been shown to attenuate NMDA receptor- the AMPA receptor antagonist NBQX was shown to attenuate
mediated neurotoxicity in neuronal cultures (Nadler et al., damages in neuronal axons and oligodendrocytes (Follett
1993). It is equally potent in vivo, as evident by a significant et al., 2000; Goda et al., 2002). While these glutamate receptor
reduction in NMDA-induced Ca2+ accumulation in rat antagonists exhibit neuroprotective effects in various models
brain when administered 3 days post-trauma (Nadler et al., of experimental TBI, they failed to improve the neurological
1995). Post-traumatic administration of HU-211 reduces BBB outcome of TBI patients in clinical trials (Maas et al., 2006, 2010;
dysfunction, brain edema, TNF-α production as well as apoptosis Jain, 2008). The discrepancy between preclinical animal study
of glial and neuronal cells (Eshhar et al., 1995; Shohami et al., and clinical trials in patients could have been due to the fact
1997). Similarly, another NMDA receptor antagonist MK 801 that glutamate-mediated excitotoxicity is an acute phenomenon

shortly after primary neuronal injury. The persistent elevated in injured axons (Buki et al., 2003; Ai et al., 2007; Czeiter et al.,
level of glutamate in traumatized human brain may instead be 2009). Similarly, the caspase-3 inhibitor Z-DEVD-fmk reduces
a neuroprotective mechanism that maintains survival of spared neuronal cell death in neuron-glial co-culture, and is sufficient
neurons, as supported by earlier reports that demonstrated for improving neurologic function and reducing lesion volumes
the pro-apoptotic role of NMDA-receptor antagonists in in induced injury in mouse and rat brain (Clark et al., 2000;
primary hippocampal neurons (Hardingham et al., 2002). In Knoblach et al., 2004).
fact, NMDAR is known to mediate both neuroprotective and
neurotoxic effects (Hardingham, 2009). The opposing function
Combating Chemical Stress to Neurons
is believed to be due to distinct properties and differential
distribution of GluN2 subunits of tetrameric NMDAR. GluN2A- and Glia
containing receptors are mainly localized to synapses, while Antioxidants
GluN2B-containing receptors are found in both synaptic and The immunosuppressive drug cyclosporine A, a potent regulator
extrasynaptic locations. GluN2A is known to be pro-survival of mPTP, has been demonstrated to have neuroprotective effects
whereas GluN2B promotes cell death following excitotoxic in experimental models of TBI (Kulbe et al., 2018). Although
glutamate stimulation (Liu et al., 2007). Blocking NMDAR the exact mechanistic action of cyclosporine A remains poorly
function in a non-discriminating manner, therefore, may not understood, its administration after TBI is associated with
reduce excitotoxicity but suppress pro-survival signals. reduced accumulation of Ca2+ through binding of the cytosolic
phophastase calcineurin to Cyp-D at mPTP. Cyclosporine
Inhibitors of Calcium Channels and treatment also inhibits the mitochondrial release of cytochrome
Calcium-Activated Enzymes c and influx of Ca2+ into mitochondria (Sullivan et al., 2005).
Hyperactivation of voltage-sensitive ion channels such as L- Furthermore, cyclosporine A exhibits anti-oxidative properties
and N- calcium channels, which causes prolonged alterations in by downregulating lipid peroxidation (Turkoglu et al., 2010).
calcium homeostasis is another important factor that contributes These effects lead to an amelioration of axonal damage and
to excitotoxicity during secondary injuries in TBI. Many calcium mitochondrial dysfunction, which result in a reduction of
channel inhibitors have in fact been demonstrated to be cortical damage and an improvement in neurological outcome
neuroprotective in experimental TBI. In a fluid percussion (Okonkwo and Povlishock, 1999; Okonkwo et al., 1999; Scheff
brain injury rat model, the calcium channel blocker SNX-111 and Sullivan, 1999; Sullivan et al., 1999, 2000, 2010; Alessandri
(Ziconotide) was found to reduce trauma-induced calcium et al., 2002; Mbye et al., 2008). Nonetheless, it should be noted
accumulation by 50–70% in the ipsilateral regions as early that a small randomized clinical trial of cyclosporine A in TBI
as 6 h post-trauma (Samii et al., 1999). Another calcium surprisingly showed no improvement in neurological outcome
channel inhibitor (S)-emopamil has been shown to reduce brain and biochemical parameters in patients as compared to healthy
edema and cerebral blood flow (Okiyama et al., 1992, 1994). individuals (Mazzeo et al., 2009). Despite this, a European multi-
Both SNX-111 and (S)-emopamil are able to ameliorate motor center phase II/III clinical trial of NeuroSTAT, a drug developed
and cognitive deficits associated with brain injury (Okiyama by NeuroViVe in which cyclosporine A is the active ingredient,
et al., 1992; Berman et al., 2000; Verweij et al., 2000). With has recently been initiated in TBI patients and the outcome is yet
a 45% amino acid similarity, SNX-185 works in a similar to be evaluated.
mechanism as SNX-111 but with improved bioavailability and Methylprednisolone is a synthetic glucocorticoid that
extended sustainability in the brain (Newcomb et al., 2000; has been widely used in clinical treatment of acute CNS
Lee et al., 2004). The L-type voltage-sensitive calcium channel injuries mainly because of its potency in anti-inflammation
antagonist nimodipine was also found to have beneficial effect and in controlling edema in injured CNS. Interestingly, a
for memory impairment in rats, though clinical trials were high dose of methylprednisolone exhibits neuroprotective
terminated because of its hypotensive effects and the lack of effects due to its anti-oxidative properties which specifically
improvement in intracranial pressure observed in TBI survivors attenuates post-traumatic lipid peroxidation. Although little
(Bailey et al., 1991; Veng et al., 2003; Maas et al., 2010). is known about the mechanism of the antioxidant effect
In addition, clinical benefits are also modest in trials of the of methylprednisolone, it is believed to integrate into the
calcium channel blocker nicardipine (Compton et al., 1990). structure of lipid bilayer and render cell membranes more rigid,
Recent studies suggested that the calpain inhibitor MDL-28170 thereby limiting the mobility of lipid peroxyl radicals (Hall,
suppresses degradation of the cytoskeletal protein α-spectrin 1992). Notably, methylprednisolone has to be administered
localized at sites of neuronal damage in both TBI and hypoxic- at initial phase of CNS injury at an optimal concentration
ischemic injury, which is associated with a reduction in necrosis to ensure maximal anti-inflammatory and neuroprotective
and apoptosis through the inhibition of calpains and caspase-3 effects. Methylprednisolone was formerly incorporated into
(Kawamura et al., 2005; Thompson et al., 2010). Pre-treatment of a randomized placebo-controlled trial known as CRASH in
TBI animals with MD-28170 also exerts neuroprotective effects 2004. A large sample size of more than 10,000 TBI patients
through the preservation of axonal structure and reduction was recruited into the study with a 2-week follow-up period.
in axolemmal leakage, as demonstrated by a decrease in Nonetheless, the outcome was undesirable with an increase
immunolabeling of APP (marker for defective axoplasmic in mortality rate (Thompson and Bakshi, 2005). In fact, rats
transport) and RMO-14 (marker for neurofilament compaction) treated with methylprednisolone also showed a significant

increase in neuronal apoptosis in the hypothalamus, pituitary proteins phospho-Akt and Bcl-XL (Yatsiv et al., 2005; Liao
and hippocampus (Chen et al., 2011; Zhang et al., 2011), et al., 2008). In addition, Bcl-2 gene expression is increased,
which are associated with memory and learning impairment with a corresponding reduction in Bax level (Liao et al., 2009).
(Chen et al., 2009). Other beneficial effects include enhanced neurogenesis, reduced
production of NO, and amelioration of brain swelling, cortical
Anti-inflammatory and Anti-apoptotic Agents tissue and axonal damage (Lu et al., 2005; Yatsiv et al., 2005;
With the ability to transmigrate and diffuse across BBB, the Cherian et al., 2007). These effects of EPO are associated
semi-synthetic tetracycline derivative minocycline has been with an improvement in cognitive and motor functions (Lu
found to exhibit anti-inflammatory and anti-apoptotic properties et al., 2005; Yatsiv et al., 2005; Xiong et al., 2010). In 2010, the
in various experimental models of neurological diseases such as neuroprotective effects of EPO in experimental TBI have been
stroke, SCI, Alzhemier’s disease and TBI. Numerous studies have successfully translated into a clinical trial involving patients
demonstrated that the neuroprotective effects of minocycline with moderate to severe TBI in a joint study between Australia
can be attributed to its inhibition of microglia activation, and New Zealand. Nonetheless, the results showed that EPO
proliferation and production of pro-inflammatory cytokines did not reduce the number of patients with severe neurological
such as IL-1β, IL-6 and TNF-α (Sanchez Mejia et al., 2001; dysfunction (Nichol et al., 2015).
Bye et al., 2007; Choi et al., 2007; Parachikova et al., 2010;
Garrido-Mesa et al., 2013). In an experimental mouse model of Promotion of Neuronal Regeneration
closed head injury, for instance, minocycline treatment causes Neurotrophic Factors
a marked decrease in IL-1β level in the cortex by 50%, with Neurotrophic factors including vascular endothelial growth
concomitant inhibition of microglia activation and improvement factor (VEGF), brain-derived neurotrophic factor (BDNF), nerve
in neurological outcome (Bye et al., 2007; Ng et al., 2012). growth factor (NGF), basic fibroblast growth factor (bFGF) and
Interestingly, minocycline treatment has been found to inhibit epidermal growth factor (EGF) are capable of determining the
matrix metalloproteinases and preserve BBB integrity, leading post-traumatic fate of neuronal and glial cells. Administration
to an alleviation of cerebral edema (Homsi et al., 2009). of these growth factors following TBI can improve neurological
Minocycline has also been shown to exhibit anti-apoptotic outcome (Wu et al., 2008; Sun et al., 2009). Exogenous VEGF, for
properties by inhibiting caspase activities (Sanchez Mejia et al., instance, increases astrocytic response, promotes angiogenesis
2001). In addition, Siopi et al. (2011) have reported that and enhances neurogenesis in experimental model of TBI
minocycline treatment results in significant restoration of the through the activation of Akt pathway and the Raf/MEK/ERK
level of neuroprotective soluble APPα 24 h post-trauma, hence cascade (Wu et al., 2008; Thau-Zuchman et al., 2010; Lu et al.,
contributing to the protection of damaged axons. A recent study 2011). VEGF also reduces apoptotic cell death and promotes
has reported that early administration of minocycline decreases neurite outgrowth via Rho-dependent pathway (Jin et al., 2006).
various inflammatory and glial protein markers such as MCP-1 Administration of NGF into the lateral ventricles or
and S100β at 51 days post-trauma, with concomitant significant parenchyma of injured adult rat brain has been shown to
improvement in locomotion, anxiety and spatial memory in an promote survival of cholinergic septal neurons and reduce
experimental rat model of mild blast TBI. This suggests that neuronal cell death, which are in accordance with the
minocycline might have a long-lasting neuroprotective effect improvement in memory retention and cognitive deficits
(Kovesdi et al., 2012). (Kromer, 1987; Dixon et al., 1997; Sinson et al., 1997). Similarly,
Erythropoietin (EPO) belongs to type 1 cytokine superfamily. exogenous infusion of BDNF contributes to improvement in
The expression of both EPO and EPO receptor is significantly histological deficits and neurological function, and promotion
upregulated in TBI, which plays an important role in of axonal regeneration in experimental models of excitotoxicity,
neuroprotection though the exact mechanisms remain elusive cerebral ischemia and SCI (Burke et al., 1994; Schäbitz et al.,
(Brines et al., 2000). It is evident that the EPO/EPOR interaction 1997; Namiki et al., 2000). It should be noted, however, that
allows phosphorylation of receptor-associated Jak-2, which in Blaha et al. (2000) have shown no improvement in memory
turn activates various signaling pathways, including caspases, loss and alterations in apoptotic cell death in both the injured
Ras/MAPK, nuclear factor Kappa B and Stat-5 (Fujitani et al., cortex and hippocampus after post-traumatic intraparenchymal
1997; Mammis et al., 2009). Intriguingly, further research infusion of BDNF. In an in vitro model of focal trauma using rat
indicated that EPO can exert neuroprotective effect in the hippocampal slice culture, bFGF and EGF treatment promotes
absence of EPO receptor. These EPO-mediated mechanisms survival of existing neurons and formation of new neurons in
are found to have prominent roles in inflammatory response the dentate gyrus, as evident by NeuN immunostaining and a
and apoptotic cell death (Yatsiv et al., 2005; Xiong et al., 2010). significant increase in BrdU-positive newborn progenitor cells,
Studies in rats have demonstrated that EPO treatment suppresses respectively (Laskowski et al., 2005). Similar beneficial effects are
neuroinflammation with evidence of significant downregulation observed when bFGF is administered into the brain ventricles of
of adhesion molecules, NF-kb and pro-inflammatory cytokines TBI rats, which results in a significant recovery of TBI-induced
such as IL-6, IL-1β and TNF-α (Chen et al., 2007), as well as neurological deficits (Sun et al., 2009).
a reduction in astrocytic response and microglia activation Infusion of bFGF to rat brain 3 h after injury induced by
(Yatsiv et al., 2005). EPO has also been shown to have lateral fluid percussion can still significantly reduce neuronal
anti-apoptotic effects by upregulation of the anti-apoptotic damage and lesion volume (Dietrich et al., 1996). In fact,

severed CNS has been found to produce various growth factors axonal regeneration. Recent studies have reported that DNA
after injuries. Chiaretti et al. (2008, 2009) showed a significant vaccines against the myelin-derived inhibitors Nogo, MAG and
upregulation of NGF in the CSF of children with severe TBI, OMgp promote axonal repair in the corticorubral projection
which correlates with an improvement in Glasgow recovery and improve neurological outcome in experimental models of
scores. An upregulation of BDNF and its receptor at the cortical TBI and stroke in rats (Zhu et al., 2007; Zhang et al., 2009).
lesion site was also observed in induced TBI in non-human Immunization of rats against Nogo receptor (NgR) after induced
primates (Nagamoto-Combs et al., 2007). Taken together, these spine injury also promotes axonal regeneration and functional
studies suggest that neurotrophic factors are able to confer recovery (Yu et al., 2007, 2008). DNA vaccination is a novel and
neuroprotection after TBI. relatively simple technique to induce an immunological response
by injection of genetically engineered DNA encoding the antigen
Suppression of RhoA GTPase into the body so as to trigger immune system in the host. These
Accumulating evidence has demonstrated that central neurons studies demonstrated that DNA vaccine against myelin-derived
have the potential to regenerate, though the process is largely inhibitors might be a promising approach to promote recovery of
suppressed by the non-permissive environment in injured CNS. injured CNS. More detailed investigation is required to validate
Recently, the small GTPase RhoA has emerged to play a the effects and to better understand the mechanistic action and
pivotal role in mediating the effect of inhibitory molecules potential side effects of these DNA vaccines.
in glial scar and damaged myelin against axonal regeneration.
Surmounting Glial Scar
Exoenzyme C3 transferase is an enzyme found in Clostridium
Recent findings suggest that glial scar not only acts as a
botulinum that ADP-ribosylates Rho proteins by transferring
physical barrier to impede axon regeneration, the complex
the ADP-ribose moiety from NAD to the acceptor amino acid
cocktail of inhibitory molecules therein such as CSPGs, tenascins
residue asparagine-41 of Rho proteins, thereby blocking the
and semaphorins also represent a non-permissive milieu for
downstream signaling that causes growth cone collapse and
axonal growth (Fawcett, 2006). Significant upregulation of
inhibition of axonal regeneration (Aktories et al., 2005). The
CSPGs like neurocan, phosphacan, versican and NG2 in glial
effect of C3 transferase in promoting axonal regeneration has
scar contributes to the failure of axon regeneration following
been extensively studied in both in vitro and in vivo animal
CNS injury. Administration of the CSPG-degrading enzyme
models of SCI and peripheral nerve injury (Tan et al., 2007;
chondrotinase ABC reduces the level of CSPGs and cavitation
Höltje et al., 2009; Boato et al., 2010; Huelsenbeck et al.,
at the lesion site within 24 h (Lin et al., 2008). In vivo studies
2012). Rats subjected to experimental SCI showed improvement
of SCI have confirmed the effect of chondrotinase ABC in
in neurological outcomes upon treatment with C3 peptide
the promotion of sprouting and outgrowth of injured axons
(Boato et al., 2010). With the same enzymatic activity as the
and the ensuing re-innervation (Bradbury et al., 2002; Yick
original C3 bacterial toxin exoenzyme, the C3 derivative BA-210
et al., 2003; Chau et al., 2004; Barritt et al., 2006). Importantly,
has been demonstrated to enhance functional regeneration in
the improvement in axonal pathology is associated with an
animal models of spine injuries (Lord-Fontaine et al., 2008).
amelioration of neurological deficits (Bradbury et al., 2002;
Importantly, it can maintain its stability after 18 months of
Barritt et al., 2006). Overexpression of chondrotinase ABC in
storage at low temperatures (Lord-Fontaine et al., 2008). The
transgenic mice has also shown regeneration of axon through
drug Cethrin/VX-210 (in which BA-210 is the active ingredient)
astrocytic scar (Cafferty et al., 2007). The inhibitory molecules
has passed phase I/IIa open-label clinical trial that assesses
in glial scar, therefore, represent promising targets to promote
its safety, tolerability and treatment efficacy in SCI patients
regeneration in TBI.
(Fehlings et al., 2011; McKerracher and Anderson, 2013), and
is currently going through phase IIb/III trial to evaluate its Stem Cell Therapies
efficacy and safety in patients with acute traumatic cervical Loss of neurons and glia are major hallmarks in severed CNS.
SCI. In addition to its key roles in promoting regeneration Replacement of these cells, therefore, represents a valid approach
of axons and neurites, C3 also regulates apoptosis through of therapy. Marrow stromal cells are capable of differentiating
interaction with p53NTR (Dubreuil et al., 2003). Given the wide into multiple cell lineages including glia and neurons both
range of cellular functions of C3 transferase in promoting CNS in vitro and in vivo (Sanchez-Ramos et al., 2000; Lu et al.,
regeneration, combinatorial therapies of C3 transferase and other 2001). Rat or human bone marrow stromal cells intravenously
neuroprotective drugs may provide additive effect (McKerracher administered into rats after TBI were found to migrate into
and Guertin, 2013). Although the significance of C3 transferase the lesioned cortex and displayed an astrocytic and neuronal
in experimental models of TBI remains to be determined, it phenotype, as identified by glial (GFAP) and neuronal (NeuN)
stands to believe that the beneficial effects observed in spine markers, respectively (Lu et al., 2001; Mahmood et al., 2004b).
injuries are also applicable to TBI given the similarities between Marrow stromal cells also play an important role in inducing
these two forms of CNS trauma. neurogenesis after TBI, as indicated by the presence of new
BrdU+ proliferating cells in the contusion, subventricular zone
DNA Vaccine Against Myelin-Derived Axonal Growth and hippocampus (Mahmood et al., 2004b). These histological
Inhibitors findings correlated with a sustained improvement of neurological
Myelin-associated axonal growth inhibitors exposed in severed and motor functions (Lu et al., 2001; Mahmood et al., 2004b).
axons are known to cause growth cone collapse and impede Similarly, mesenchymal stem cells also exhibit beneficial effects

in both in vitro and in vivo TBI studies. Mesenchymal stem replacement of severed neurons but also through the promotion
cells isolated from mice promote proliferation and induce GFAP of survival and proliferation of resident cells via paracrine release
expression in neural stem cell culture. Injection of mesenchymal of bioactive molecules or direct cell-cell interaction (Chen et al.,
stem cells into acute TBI model reduces the expression of various 2002; Mahmood et al., 2004a). In this regard, exosome released
pro-inflammatory cytokines and chemokines such as IL-1β, IL-6, from MSCs has emerged as promising candidate that mediates
TNF-α, CCL2, CCL11 and CXCL (Galindo et al., 2011). In these beneficial effects. Systemic administration of cell-free
addition to anti-inflammatory effect, mesenchymal stem cells exosomes released by MSCs was found to promote restoration
attenuate neuronal loss in the hippocampus and cortex through a of cognitive and sensorimotor functions in rat TBI model,
reduction of caspase-3 activation and an increase in AKT activity concomitant with neurovascular remodeling, neurogenesis in
(Kim et al., 2009). Human mesenchymal stem cells have also been the dentate gyrus and reduced neuroinflammation (Zhang
shown to improve neurological function in TBI rats 2 weeks after et al., 2015). Intravenous infusion of exosomes isolated from
transplantation (Kim et al., 2009). MSCs can also suppress neuroinflammation, improve cognitive
Stem cells from human are used in many studies due to and spatial learning functions in mouse after TBI (Kim
the capability to release neurotrophic factors such as NGF et al., 2016). Exosomes are small membrane vesicles with
and BDNF, which are known for their neuroprotective effects. diameter ranging from 50 to 200 nm (Trams et al., 1981;
Transplantation of human fetal stem cells, for instance, leads Schneider and Simons, 2013). They carry proteins, RNAs,
to sustained improvement in motor function and memory, microRNAs, lipids, and exert intercellular signaling function
which is associated with a reduction in lesion volume and by transferring these cargoes to other cells via ligand-receptor
neuronal loss at the lesion site (Riess et al., 2002; Skardelly binding and internalization (Taylor and Gercel-Taylor, 2014).
et al., 2011). These can also be attributed to the promotion of For instance, exosomes released from injured sensory neurons
angiogenesis and inhibition of activated microglia post-injury are enriched in miR-21, a non-coding microRNA that upon
(Skardelly et al., 2011). Importantly, fetal stem cells were found to phagocytosed by macrophages promotes pro-inflammatory
differentiate into neurons and astrocytes in injured hippocampus responses. Administration of antagomir against miR-21 reduces
and cortex with the release of glial-derived neurotrophic factor neuropathic hypersensitivity and recruitment of inflammatory
(Riess et al., 2002; Gao et al., 2006). A small scale phase I macrophages to the injury site (Simeoli et al., 2017). By contrast,
clinical trial on autologous marrow stromal cell transplantation miR-21 in exosomes released from neurons formerly primed
in young TBI patients has shown no adverse effects though by injured mouse brain extracts have recently been shown to
only modest neurological improvement was found (Cox et al., inhibit the activity of neuronal autophagy (Li et al., 2019).
2011). Tian et al. (2013) conducted a phase I/II trial in patients Furthermore, exosomes enriched in miR-17–92 cluster have been
with sub-acute phase of TBI by intrathecal administration of shown to promote neurogenesis, oligodendrogenesis, and axonal
autologous bone marrow-derived mononuclear cells. While no outgrowth in severed CNS due to stroke (Xin et al., 2017).
major complications were observed, improvement in function miR-132 carried by exosomes acts as an intercellular signal
was only seen in less than half of the patients with persistent to regulate brain vascular integrity (Xu et al., 2017). In short,
vegetative state and motor disorder (Tian et al., 2013). Expansion exosomes derived from neurons and glial cells can regulate gene
of this study by recruiting more subjects will provide insight into expression and miRNA activities in an autocrine manner, which
the feasibility of this approach. in general mediate neuroprotection and neurorestorative effects
by promoting neurogenesis, reducing inflammation, increasing
Extracellular Vesicles and miRNAs angiogenesis and tissue remodeling.
While stem cell therapies have demonstrated promising effects in
promoting regeneration in TBI, these treatments are associated DELIVERY OF THERAPEUTIC AGENTS TO
with various complications. The use of fetal embryonic stem cells THE BRAIN
undoubtedly involves legal and ethical issues. Multipotency of
stem cells poses the risk of unregulated growth and tumorigenesis Overcoming Physiological Barriers
(Jeong et al., 2011). Administration of these cells into the Physiological barriers such as the BBB and the blood-CSF barrier,
body may also occlude microvasculature and trigger immune maintained by endothelial cells separating the CNS from the
responses (Furlani et al., 2009). Besides, it is laborious to isolate, peripheral circulation, are of great importance in protecting the
prepare and preserve viability of stem cells. As stated above, brain. These interfaces tightly regulate the transmigration of
mesenchymal stem cells have recently emerged as promising small molecules into the CNS, hence posing challenges to drug
candidates for TBI treatment. MSCs administered into the delivery in TBI treatment. It should be noted, however, that
body were found to preferentially migrate to damaged tissue BBB intactness is often compromised as a direct consequence of
sites where they differentiate into neurons and glial cells, TBI. While BBB dysfunction contributes greatly to the prolonged
reducing expression of axon outgrowth inhibitory molecules, secondary damage after TBI, it also allows therapeutic proteins
suppressing neuroinflammation and promoting the release of or peptides administered through other entry routes such as
growth factors, with concomitant substantial improvement intranasal delivery to cross the tight endothelial junctions and
in neurological functions (Das et al., 2019). Interestingly, reach the injury site (Habgood et al., 2007; Lotocki et al.,
accumulating evidence suggests that the protective effect of 2009; Ligade et al., 2010). In experimental TBIs, intraventricular
MSCs may not be entirely due to their differentiation and administration of therapeutic agents is a common and feasible

method to overcome these barriers by direct delivery into the confirmed to be compatible with the nervous system. Depending
CSF (Temsamani et al., 2000). In clinical management of TBI, on the application, PLGA polymers can be prepared in different
surgical intervention is often required to relieve intracranial dosage forms by using specific techniques (Anderson and
pressure and edema, which also provides an opportunity for Shive, 1997; Soppimath et al., 2001). The emulsification solvent
direct drug delivery. evaporation method, for instance is widely used in fabricating
PLGA microspheres (Jain, 2000). Recently, the electrospinning
Sustained and Controlled Drug Delivery via technique has been developed to produce nanofibers (Li et al.,
Osmotic Pumps 2002). Both of these methodologies allow high efficiency of drug
While the therapeutic agents discussed above demonstrate incorporation during the production process. Tan et al. (2007)
various neuroprotective effects in both in vitro and in vivo have demonstrated >80% loading efficiency in the encapsulation
studies of TBI, the long-lasting adverse effects associated with of the recombinant protein Tat-C3 transferase, a potent RhoA
secondary brain damage calls for the development of delivery inhibitor that freely enters cells, in PLGA microspheres using
systems that allow constant, sustained, and controlled release the water-in-oil-in-water emulsification method (Tan et al.,
of these candidate therapeutics to exert their full potential in 2007). Alternatively, drugs can be adsorbed onto pre-fabricated
promoting recovery from TBI. In experimental models of TBI in polymer particles.
rats, osmotic mini-pumps have been successfully used to deliver Drug release from PLGA-based depot involves gradual
NGF and S100B neurotrophic protein into lateral ventricles in degradation of the polymer when hydrogen and covalent bonds
the brain at a constant rate, which results in promotion of are hydrolyzed by water to form lactic and glycolic acids,
cognitive functions (Dixon et al., 1997; Kleindienst et al., 2004). which can be metabolized by Krebs cycle in the body (Park,
These mini-pumps are implantable and require no external 1995). Manipulating the ratio of lactide to glycolide monomers
power as they are driven by the pressure developed from osmotic in the polymer allows modulation of the degradation profile,
difference between osmolytes in the pump and interstitial fluid hence the rate of drug release. A higher glycolide content,
of the body. The capability to continuously infuse drugs at a rate for instance, correlates with faster hydrolysis and drug release.
of microliters per hour from 1 day to a month renders osmotic Other contributing factors include physico-chemical properties
mini-pump a powerful tool to evaluate the in vivo efficacy and of the polymer such as solubility, porosity and molecular
toxicity of agents that have a short half-life, like proteins and weight (Anderson and Shive, 1997). In addition, polymers that
peptides, though subcutaneous implantation of the pump is are end-capped with esters are more resistant to hydrolytic
needed to minimize infection and allow unrestrained movement degradation than those with free carboxylic acid. In the in vitro
of the subject. study by Tan et al. (2007), PLGA polymers carrying uncapped
(free carboxyl) and capped (lauryl ester) end groups were blended
Nanocarriers at various ratios to determine the optimal release profile for
In addition to osmotic pumps, encapsulation of drugs in the encapsulated recombinant protein Tat-C3. Release kinetics
micro- or nanoparticles is emerging as promising ways analysis revealed that the formulation of 30% capped-70%
to allow sustained and controlled delivery of therapeutics in uncapped PLGA allowed a mild initial burst while maintaining
TBI research. Both natural and synthetic polymers have been constant rate of protein release over a period of 28 days.
successfully used as drug depots, which share common features The protein release characteristics were a result of balanced
of being biocompatible, biodegradable, generally inert, as well degradation rate of capped and uncapped PLGA, as well as the
as capable of attaching to or encapsulating small molecules concomitant gradual increase in porosity of the microspheres
and proteins (Orive et al., 2009). While biopolymer-based drug due to formation of new internal pores within existing pores as
delivery systems have been applied in many tissues and organs, revealed by scanning electron microscopy (Tan et al., 2007).
reports of their use in TBI treatment is limited (Heile and Since in vivo application of biopolymer-based drug delivery
Brinker, 2011; Guan et al., 2013; Khalin et al., 2016). Turkoglu systems involves direct and prolonged contact with tissues, one
et al. (2010) have administered cyclosporine A-loaded natural of the major concerns is their biocompatibility, which can be
chitosan microspheres into brain ventricles after TBI induction determined according to the inflammatory responses induced
in rats. While it successfully reduced mitochondrial damage and after implantation into different sites of the brain, such as the
lowered lipid peroxidation, the beneficial effect was, in fact, striatum, lateral ventricles, frontal lobe and substantia nigra
comparable to that of the control group where cyclosporine (Fournier et al., 2003; Lampe et al., 2011). While PLGA polymers
A alone was intraperitoneally injected (Turkoglu et al., 2010). are generally known to be biocompatible, some studies have
This could have been due to the sub-optimal formulations reported that they induce acute inflammatory responses, as
of chitosan microspheres, dosage of the drug and route of detected by immunohistochemical staining of astrocytes though
administration. Other natural biopolymers commonly used for it could be a non-specific consequence of mechanical trauma
drug encapsulation include alginate and gelatin (Orive et al., (Emerich et al., 1999; Lampe et al., 2011). A known issue of PLGA
2009). One of the most popular synthetic biopolymers used polymers is their adverse effects on the stability of encapsulated
as nanocarriers for drug delivery purposes is the family of proteins or peptides. Loss of protein activity or integrity during
poly (D,L-lactide-co-glycolide; PLGA), polylactic acid (PLA) and the controlled released process can be attributed to protein
polyglycolic acid (PGA). Notably, these polymers are approved adsorption to the polymer, or to a greater extent protein
by the Food and Drug Administration in the US and are denaturation due to acidification when PLGA polymers break

down to lactic and glycolic acids. The stability of encapsulated neurons, microglia, and oligodendrocytes in the brain (Alvarez-
bioactive agents can be improved by incorporating pH modifiers Erviti et al., 2011). Since exosomes are stable and can preserve
such as calcium carbonate or magnesium hydroxide during the the conformation and bioactivity of proteins and nucleic acids,
encapsulation process (Houchin and Topp, 2008). Similarly, they serve as ideal natural vehicles for targeted drug delivery
proton scavengers/sponge that are basic amines, such as 1–8- to the CNS.
bis-(dimethylamino)naphthalene can be added as excipients
(Houchin et al., 2007). Furthermore, recent studies have reported Cell Penetrating Peptides to Facilitate Cell
inactivation of encapsulated peptides by an acylation reaction Entry of Drugs
of their reactive amines with the ester bonds of PLGA (Domb While the issues of sustained and controlled delivery of
et al., 1994). PEGylation of the peptide prior to encapsulation drugs can be resolved by various approaches described above,
can prevent these undesirable covalent interactions with PLGA therapeutic agents such as peptides or proteins directed against
(Na and DeLuca, 2005). The resulting PEGylated peptides also intracellular targets often encounter difficulties in gaining access
exhibit reduced immunogenicity. into cells because of their low membrane permeability. To
improve the efficiency of cell entry, these proteins can be
Extracellular Vesicles for Drug Delivery fused to a peculiar class of proteins known as cell penetrating
Exosomes are lipid bilayer membrane vesicles released by almost proteins (CPPs), which are capable of traversing biological
all cell types. Cargoes carries by exosomes are mainly molecules membranes and act as cellular delivery vehicles (Koren and
derived from endosomes, ranging from mRNAs, microRNAs, Torchilin, 2012; Guidotti et al., 2017). CPPs, also commonly
proteins to lipids, which vary based on cell origin (Chopp and known as protein transduction domains, are small amphipathic
Zhang, 2015). Recently, exosomes derived from MSCs have peptides that contain mainly positively charged amino acids
received attention due to their effect in promoting functional like arginine and lysine. Different unique properties and nature
recovery in animal models of TBIs (Zhang et al., 2015). of these CPPs allow non-invasive internalization of conjugated
Although the underlying mechanism is not fully understood, peptides or small molecules through the plasma membrane
miRNAs transferred from exosomes seemingly play a pivotal (Gupta et al., 2005; Foged and Nielsen, 2008). Despite extensive
role in mediating the beneficial effect (Taylor and Gercel- characterizations of these CPPs, the exact mechanism through
Taylor, 2013). Importantly, the unique property of exosomes as which they permeate the plasma membrane is still controversial
natural lipid-based nanovesicles that show high biocompatibility, and remains to be determined. Multiple mechanisms of cellular
low immunogenicity, efficient permeability across BBB and internalization have been proposed in CPPs, and the efficiency of
cell membrane renders them promising candidates to be translocation appears to be dependent on the nature of individual
developed as novel drug delivery system for CNS (Xiong CPP (Koren and Torchilin, 2012). For instance, CPPs conjugated
et al., 2017). Accumulating evidence suggests that exosomes with target peptides can directly translocate across lipid bilayer
transverse through membranes via ligand-receptor binding and through the formation of pores at the membrane. Alternatively,
internalization. Macrophage exosomes, for instance, express CPP-mediated internalization can be via energy-dependent
the integrin lymphocyte function-associated antigen 1 (LFA- endocytosis. Lastly, the CPP-cargo fusion proteins can form
1) on surface, which interacts with the highly upregulated vesicles and inverted micelles which are capable of destabilizing
intracellular adhesion molecule 1 (ICAM-1) on endothelial cell membrane, thus releasing the conjugated proteins into cell.
cells of BBB in inflamed brain. Intravenous administration Specific cationic CPPs can bind to cell surface proteoglycans
of macrophage exosomes pre-loaded with BDNF has been (heparin sulfates) for internalization of the cargo (Foged and
shown to successfully deliver the protein to the brain (Yuan Nielsen, 2008; Sebbage, 2009). Both in vitro and in vivo
et al., 2017). Exosomes derived from choroid plexus epithelial studies of CNS injuries have demonstrated successful cellular
cells express folate receptor α (FRα), which interacts with translocation of different proteins by conjugating to various
ependymal cells and mediates transverse through the CSF-brain CPPs, including trans-activating transcription (Tat) factor,
barrier before being taken up by astrocytes and neurons in penetratin, membrane translocating sequences, transportan and
the brain (Grapp et al., 2013). These observations suggest that Pep-1 (Lindgren et al., 2000). Nonetheless, the concerns about
receptor-mediated transcytosis of exosomes can be a promising cytotoxicity and specificity of these CPPs remain controversial.
way for drug delivery to the CNS. Apart from using natural While majority of studies have indicated a low level of toxicity of
exosomes which intrinsically expressing protein or lipid ligands CPPs at low concentrations, high cytotoxicity has been reported
that bind to intended recipient cells, exosomes can also be in rat neuronal cultures (Antoniou and Borsello, 2010). Further
engineered to target particular cell types or tissues by ectopic validation of the biocompatibility of CPPs is therefore required.
expression of specific ligands or homing peptides. Alvarez-
Erviti et al. (2011) forced expressed a fusion protein between DISCUSSION
the exosomal membrane protein Lamp2b and the neuron-
specific RVG peptide in exosomes isolated from dendritic cells. Research in traumatic injuries in the CNS has significantly
Purified exosomes were then loaded with siRNA directed against expanded our understanding of the underlying pathophysiology
GAPDH and systemically introduced into mice via intravenous and molecular mechanisms. While primary injuries in TBI are
injection. Strikingly, exosome-mediated delivery of these siRNAs largely irreversible, the ensuing secondary damages that develop
was found to successfully downregulate the target mRNA in and progress over months to years are amenable to therapeutical

interventions. Since this delayed phase of injury involves a non-cytotoxic concentration. TBI has become a major health and
plethora of events, which include excitotoxicity, apoptotic cell socioeconomic problem throughout the world, which imposes
death, inhibition of axonal regeneration, neuroinflammation and a significant healthcare burden to modern societies that call for
oxidative stress, the devise of efficacious therapeutic strategies more effective therapeutic means. It also represents a valid issue
will need to target multiple mechanisms over an extended period. in defense science because of a drastic increase in subtle CNS
The availability of depot systems for regulated and sustained injuries among the military when they are better protected from
delivery of therapeutic agents that are capable of entering cells fatality by modern technologies.
by permeating the plasma membrane will apparently allow
further improvement of the bioavailability of existing drugs. AUTHOR CONTIBUTIONS
More importantly, it will offer the opportunity to explore
the therapeutic potential of novel agents against druggable All authors listed have made a substantial, direct and intellectual
targets. In fact, this therapeutic approach has been applied contribution to the work, and approved it for publication.
in the treatment of many neurodegenerative disorders such
as Alzheimer’s disease, Huntington’s disease and Parkinson’s FUNDING
disease (Popovic and Brundin, 2006; Saraiva et al., 2016). While
the feasibility of this strategy in the management of TBI has yet This work was supported by the National Medical Research
to be established, it seems promising due to the slow progression Council, Singapore, Fundamental Research Grant Scheme,
of events during secondary damages in TBI, which require Ministry of Education, and the eScienceFund, Ministry of
continuous availability of therapeutic agents in bioactive form at Science, Technology and Innovation, Malaysia.
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Traumatic Brain Injuries: Pathophysiology and Potential Therapeutic Targets

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published: 27 November 2019

Traumatic Brain Injuries:

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Pathophysiology Therapeutic targets Potential therapies Clinical trials Treatment efficacy

Ca2+ channel inhibitors

Neuroinflammation Pro-inflammatory Anti-inflammatory agents Minocycline: NCT01058395; Anti-inflammatory and

Axonal degeneration Calpains, NOS Glutamate receptor antagonists Anti-apoptotic,

Frontiers in Cellular Neuroscience | www.frontiersin.org 7 November 2019 | Volume 13 | Article 528

Patho-physiology Therapeutic targets Potential therapies Clinical trials Treatment efficacy

Stem cells therapy

Apoptosis Caspases, calpains, Calpain/caspase inhibitors Anti-apoptosis

Stem cells therapy

Impaired mTOR Rapamycin (Erlich et al., 2007; Neuroprotection

RhoA inhibitors Cethrin (BA-210: Treatment of SCI patients with

Glial scar CSPGs, tenascins, Glial scar Chondrotinase ABC

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